Cancer-driving genetic mutation does not always cause disease

Researchers have found that a genetic mutation associated with a rare group of blood cancers does not always result in development of the disease. The work provides insight into the initial phases of the disease and may eventually lead to tailored monitoring techniques that improve patient outcomes.

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are a group of blood cancers that cause the overproduction of red blood cells, some types of white blood cells, or platelets. Many cases of MPNs are driven by a particular mutation in the gene JAK2, called JAK2V617F.

We were fortunate to have access to a population study that allowed us to look at the occurrence of this mutation in the general public. That allowed us to see relationships between the mutation and instances of disease."

Jordan Snyder, assistant teaching professor of mathematics, North Carolina State University and corresponding author of the study

Snyder was formerly an assistant professor of mathematics at Roskilde University, Denmark, where the work was done.

The researchers looked at participant data from the Danish General Suburban Population Study, which contained blood samples and health questionnaires completed by residents of Zealand, Denmark. Of the nearly 20,000 participants, Snyder's group identified 67 people with the JAK2V617F mutation.

"Specifically, we were able to get data on the participants' variant allele fraction, or VAF, over a 10-year period from a sample of the general public, not just patients," Snyder says.

"Every cell that has DNA has two copies of JAK2, but not every copy has the same mutation status," Snyder continues. "VAF represents the number of mutated copies of the gene versus normal copies. Most of the work around this mutation is looking at the VAF of patients with cancer. But to figure out how the disease progresses from a healthy state, we need to look at VAF before cancer develops."

The research team created a stochastic mathematical model to describe how the mutation might proliferate in blood stem cells, where it is believed to originate. According to the model, in 70% of cases the mutated cells were likely to outcompete their normal counterparts; in 18% of cases mutants had a competitive disadvantage compared to normal cells; and 12% showed neither an advantage nor a disadvantage.

Thirty-seven of the 67 people in the study with the JAK2V617F mutation were later diagnosed with an MPN blood cancer, fewer than might be expected based on previous research.

"While the exact mechanism of action from this mutation is not completely understood, the previous assumption was that the mutation would always eventually out-compete healthy copies, leading to cancer," Snyder says. "But these data point to the idea that there is more to it. It's not just the presence of the mutated gene - something is happening to help that mutated copy out-compete the normal ones.

"Next steps in this work will be looking at some of those potential other factors - such as chronic inflammation."

The research appears in Proceedings of the National Academy of Sciences and was supported in part by the Lundbeck Foundation Fellowship under grant R335-2019-2300. Johnny Ottesen of Roskilde University and Thomas Stiehl of Roskilde University and RWTH Aachen University are co-senior authors. Other Roskilde University contributors include Morten Andersen and Johanne Gudmand-Høyer. Morten Kranker Larsen, Vibe Skov, Lasse Kjær, Christina Schjellerup Eickhardt-Dalbøge, Trine A. Knudsen, Christina Ellervik, and Hans C. Hasselbalch of Zealand University Hospital made up the clinical research team that designed the study and collected the data.